Introduction
Observational studies have associated cholecystectomy with cardiometabolic disorders and colorectal cancer. This is of clinical importance as the case volume of cholecystectomy has increased exponentially and cardiometabolic disorders pose a significant health burden. Understanding post-cholecystectomy gut microbiome changes may help clarify some of these observations. Published data on cholecystectomy-related gut microbiome changes are limited and mainly cross-sectional in study design, lack adequate taxonomic resolution or prediction of functional pathways as 16S rRNA sequencing rather than shotgun metagenomics sequencing was used, and observed microbiome changes have not been correlated with concomitant changes in the metabolome1.
Aims & Methods
This exploratory prospective cohort study aimed to examine the changes in gut microbiome and systemic metabolome post-cholecystectomy. Subjects aged 21 to 65 years undergoing cholecystectomy for treatment of symptomatic gallstone disease were enrolled. Exclusion criteria included the use of antibiotics or probiotics within one month, appendicectomy, bowel surgery and inflammatory bowel disease. Biospecimens (stool, plasma and urine) were collected at baseline and one-month post-cholecystectomy. Stool microbiome was analysed by shotgun metagenomics sequencing, with assessment of 𝜔2 effect size (derived from weighted Jaccard distance), α (Mann-Whitney U test for unpaired and Wilcoxon signed-rank test for paired tests) and β diversity indices (PCoA and PERMANOVA), as well as differentially abundant bacterial taxa and functional pathways (Maaslin2 R package, using false discovery rate [FDR] < 0.1). Systemic metabolome (plasma, stool and urine) was examined by targeted liquid chromatography-mass spectrometry, and Orthogonal Partial Least Squares Discriminant Analysis was performed to identify metabolites that were different post-cholecystectomy, using paired t-tests and FDR < 0.1. Correlation analysis of changes in stool microbiome and metabolome was performed.
Results
A total of 26 subjects were enrolled. The mean age was 47 years (12), with 62% (16/26) male and mean body mass index (BMI) 25.57 kg/m2 (3.75). Other clinical meta-data were smoking in 15.4% (4/26), alcohol consumption in 11.5% (3/26), use of proton pump inhibitors (PPI) in 7.7% (2/26), statins usage in 23.1% (6/26), and presence of fatty liver in 15.4% (4/26). The microbiome profile of the enrolled cohort was similar to matched asymptomatic controls with intact gallbladder (with or without gallstones). One-month post-cholecystectomy, the 𝜔2 effect size was 0.006 (80% power, α < 0.05). Significant differences were observed for β diversity indices after controlling for drinking status, presence of fatty liver and use of PPI. There were 32 differentially abundant bacterial taxa and 124 differentially abundant functional pathways. Analysis of observed microbiome and systemic metabolome changes revealed correlation of 9 species with plasma bile acid (chenodeoxycholic acid [CDAC]), 20 species with plasma lipids, 3 species with stool bile acids (CDCA), 9 species with stool carboxylic acids and 2 species with urinary trimethylamine N-oxide.
Conclusion
Cholecystectomy resulted in significant changes in the stool microbiome and systemic metabolome. Such changes may help explain the epidemiological association with cardiometabolic disorders. Further larger scale prospective cohort studies with longer duration of follow-up are needed to confirm these observations.
References
1. Ang TL, Koo SH, Ang D, Tan CK, Wang LM, Wong SH, Chow PKH. Postcholecystectomy Gut Microbiome Changes and the Clinical Impact: A Systematic Review With Narrative Synthesis. J Gastroenterol Hepatol. 2025 Mar;40(3):574-583.